Project Summary/Abstract Several neurodegenerative disorders, including Parkinson?s and Alzheimer?s diseases, display alterations in the function of the endocannabinoid (eCB) system. In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is now considered a chronic disease with an inflammatory component that specifically targets the brain and causes a high prevalence of HIV-associated neurocognitive disorders (HAND). The eCB system has attracted interest as a target for treatment of neurodegenerative disorders, due to the potential neuroprotective, anti-inflammatory, & neurotrophic properties of CBs. However, therapeutic use of eCBs in vivo is unlikely due to their rapid degradation by catabolic enzymes. The main enzymes responsible for degradation of two major eCBs, anandamide (AEA) and 2-arochinonoylglycerol (2- AG), are respectively: fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MAGL). A new class of selective inhibitors of those enzymes has been developed that show neuroprotective and anti-inflammatory effects in preclinical animal models of neurodegenerative diseases. These new pharmacological tools allow for selective elevation of eCB signaling, which enables investigation of physiological actions of particular eCBs as well as reveal therapeutic potential of such precise modulation. The aim of the present study is to unravel the role of the eCB signaling in neuroprotection against HIV-1 protein toxicity that results in behavioral changes as a consequence of HAND. To achieve this goal, we plan to use Tat and gp120 transgenic (tg) mice, as well- established models of neuroAIDS, that will allow us to determine: 1) the neuroprotective effects of eCBs on prefrontal cortex (PFC)-dependent behavior in vivo, with use of catabolic enzyme inhibition; 2) the mechanisms underlying protective effects of eCBs in PFC ex vivo; and 3) the effects of chronic eCB catabolic enzyme inhibitors on neuroinflammation using positron emission tomography (PET) imaging in vivo. We hypothesize that in the HIV-1 protein tg mouse models, eCB catabolic enzyme inhibitors will show protective effects on behavior, function, and structure via a CB1R/CB2R-mediated mechanism. In Specific Aim 1, Tat tg mice will be trained on the operant conditioning Go/No-Go task and eCB enzyme inhibitors will be tested for protective effects against Tat-induced interference in cognitive function, including a decrease of behavioral inhibition and increased impulsivity. Moreover, the same animals will undergo electrophysiology studies on PFC pyramidal neurons ex vivo to establish the effects of eCB enzyme inhibitors on synaptic currents. In Specific Aim 2, we will conduct behavioral, functional, and morphological imaging studies to determine if eCBs are neuroprotective in Tat toxicity via a CB1R/CB2R-mediated mechanism ex vivo. In Specific Aim 3, non-invasive longitudinal PET imaging studies in Tat and gp120 tg mice will investigate the effects of eCB enzyme inhibitors on active inflammatory processes using the tracer [18F]-PBR111. Understanding the role of the eCB system in neuro- AIDS may uncover novel therapeutic targets for HAND and other diseases in which cognitive deficits occur.